Abstract
Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that inflammation may contribute to the pathogenesis of the systemic effects of alveolar hypoxia. While the role of alveolar macrophages in the immune and defense functions of the lung has been long known, recent evidence indicates that activation of alveolar macrophages causes inflammatory disturbances in the systemic microcirculation. The purpose of this review is to describe observations in experimental animals showing that alveolar macrophages initiate a systemic inflammatory response to alveolar hypoxia. Evidence obtained in intact animals and in primary cell cultures indicate that alveolar macrophages activated by hypoxia release a mediator(s) into the circulation. This mediator activates perivascular mast cells and initiates a widespread systemic inflammation. The inflammatory cascade includes activation of the local renin-angiotensin system and results in increased leukocyte-endothelial interactions in post-capillary venules, increased microvascular levels of reactive O2 species; and extravasation of albumin. Given the known extrapulmonary responses elicited by activation of alveolar macrophages, this novel phenomenon could contribute to some of the systemic effects of conditions featuring low alveolar PO2.
Highlights
Reduced alveolar PO2 is observed in a number of clinical settings, and is frequently associated with systemic effects, many of which present an inflammatory component
The results show that reduced tissue PO2 and activation of resident tissue macrophages are not necessary to initiate the systemic inflammation of alveolar hypoxia
The lung as a target of systemic hypoxia or ischemia This review addresses a novel phenomenon, the systemic inflammation elicited in response to activation of alveolar macrophages, the stimulus in this case being a reduction of alveolar PO2
Summary
Reduced alveolar PO2 is observed in a number of clinical settings, and is frequently associated with systemic effects, many of which present an inflammatory component. Rophages activated by hypoxia release a mediator into the circulation; this mediator activates mast cells which, in part at least through activation of the RAS, induce systemic inflammation If this sequence of events is correct, several conditions must apply: Alveolar macrophages, but not resident tissue macrophages, are directly activated by low PO2 Indirect evidence that alveolar macrophages are activated by hypoxia is provided by the observation that supernatant of hypoxic alveolar macrophages initiates an inflammatory response in skeletal muscle [47] and in mesentery [48]. The pulmonary response in this case is characterized by leukocyte recruitment, alveolar macrophage activation, endothelial and epithelial cell damage, increased vascular permeability and pulmonary edema [61] Both the systemic effects of alveolar macrophage activation and lung injury secondary to intestinal ischemia/reperfusion-feature remote inflammatory responses elicited by a mediator transported from a distant site. While the specific cellular pathways and the modes of translocation of inflammatory agents vary in different conditions, these examples point out to an important phenomenon, namely the production of inflammatory responses initiated from remote sites, an issue of important clinical significance
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